Redefining Success for VAP: 360-Degree Approach

BACKGROUND: Ventilator-associated pneumonia (VAP) in hospital intensive care units (ICUs) is associated with high morbidity and mortality. Effective treatment of VAP can be challenging due to a high prevalence of Pseudomonas aeruginosa and multidrug-resistant (MDR) pathogens as causative organisms. OBJECTIVE: To present the etiology of VAP in the United States (including national resistance trends of common nosocomial pathogens) and review dosing strategies aimed to optimize pharmacokinetic-pharmacodynamic parameters of antimicrobial agents. SUMMARY: The majority of nosocomial pneumonia cases are caused by gram-negative pathogens, most commonly P. aeruginosa, Enterobacter spp., A. baumannii, and K. pneumoniae. S. aureus is the most common gram-positive pathogen, with 55% of VAP isolates exhibiting methicillin resistance. Combination therapy is recommended when MDR pathogens and P. aeruginosa are suspected, although short-course therapy and de-escalation should be considered when appropriate to reduce the risk of resistance. Optimized dosing strategies are important in increasing the probability of achieving successful outcomes. For example, when administering intravenous β -lactam therapy, prolonged infusion can be effective in increasing the T > MIC. CONCLUSION: Clinicians need to be familiar with local antibiograms as well as regional resistance trends in order to choose appropriate therapy for VAP. Optimized dosing strategies can be effective in increasing the probability of attaining pharmacokinetic-pharmacodynamic targets predictive of successful clinical outcomes

listed a number of conditions (including catheter-associated urinary tract infection and vascular-catheter-associated infection) that it will no longer reimburse. 6 This will put added pressure on institutions to minimize these infections and limit the resources used to manage patients with these infections. Although VAP is not included in the current CMS listing, this could change as funding shrinks and other preventable conditions are targeted for nonreimbursement.

VAP: Goals of Successful Management Strategy
It is estimated that approximately 38% to 70% of VAP episodes can be prevented. 4 Thus, even in ideal situations, hospitals and ICUs will be confronted with a number of VAP episodes. Once a VAP case is identified, it will be important to achieve multiple goals for successful management ( Figure 1).
The most important goal of a VAP management strategy is to achieve improved clinical outcomes and reduce morbidity and mortality. This can be achieved through early appropriate antimicrobial therapy. The second goal is to reduce the emergence of bacterial resistance. This is important, as infections caused by resistant pathogens are associated with increased morbidity, mortality, and cost, while the number of agents effective against MDR nosocomial pathogens is diminishing. 7,8 The third goal of a VAP management strategy is to improve resource utilization.
Each of these goals is interrelated. If the first 2 goals are achieved through early appropriate antimicrobial therapy, this may reduce the hospital resources needed to successfully treat the patient, particularly by reducing hospital length of stay. The use of this clinical disease management approach coupled with other strategies, such as short-course or de-escalation of therapy, may provide additional opportunities to reduce overall hospital costs. These specific strategies, by reducing the unnecessary use or overuse of antimicrobials, may further reduce the risk of development of resistance.
What Is the 360-Degree Approach to Defining Success for VAP?
David P. Nicolau, PharmD, FccP, FIDSa VAP: Magnitude of the Problem Nearly 1.6 million hospital-acquired infections (HAIs) occur annually in the United States (Table 1). 1 Predominant among these HAIs are urinary tract infections, bloodstream infections, surgical site infections, and hospital-acquired pneumonia (HAP). Of these, HAP is associated with the greatest infection-related morbidity and mortality. 1 In the intensive care unit (ICU) setting, HAP accounts for 25% of all HAIs. 2 Furthermore, nearly 90% of HAP cases occur during mechanical ventilation-this subcategory of HAP is referred to as ventilator-associated pneumonia (VAP). 2 Although VAP was originally thought to be restricted to the ICU setting, this disease process is increasingly prevalent in non-ICU populations, as severely ill patients are being managed in other care areas (i.e., transitional care, long-term rehabilitation units, etc). Therefore, prevention and management of VAP is a concern for all health care personnel.
The need for mechanical ventilation in these critically ill populations means that these patients will be at an increased risk for the development of pneumonia. This risk increases as the duration of mechanical ventilation increases-estimated at a 3% increase in incidence for each day during the first 5 days of mechanical ventilation. 2 Therefore, it is paramount to employ strategies to minimize the development of VAP. 3 First and foremost among these is to identify patients who can be extubated as soon as possible to prevent VAP from occurring. Despite these efforts, a small proportion of the ventilated patient population will develop VAP. Given the high mortality associated with VAP, early appropriate therapy is critical for achieving successful outcomes for these patients. 4 Selecting appropriate therapy can be challenging, as the nosocomial epidemiology of VAP can be diverse among differing patient populations or care settings. Moreover, the identified pathogens in this infected population commonly express resistance or multidrug resistance (MDR) to antimicrobials. 5 Therefore, clinicians must recognize risk factors for infections caused by resistant organisms and be familiar with not only the epidemiology related to their patient population, but must also know the susceptibility profile of these pathogens if early appropriate therapy is to be initiated.

Prevention and Appropriate Management to Reduce Health Care Spending
HAIs have gained renewed attention as a targeted area to reduce health care spending, improve resource utilization, and achieve better patient outcomes. Insurance providers will continue to evaluate ways to conserve health care spending in hospitals and may follow the lead of recent government mandates regarding preventable hospital-acquired conditions.
The Center for Medicare and Medicaid Services (CMS) has

What This Supplement Addresses
This supplement reviews tactics that can be used to achieve the 3 goals for success in VAP. Dr. David Burgess reviews the epidemiology of VAP, highlighting the importance of local epidemiology and antibiograms of the institution and specific hospital wards. Dr. Burgess continues his discussion on using pharmacokinetics and pharmacodynamics as the basis for optimizing antimicrobial dosing to reduce the risk of resistance emergence.
Dr. Keith Rodvold emphasizes the importance of efficiently using the available resources when managing patients with VAP. The clinical and economic burden of VAP is substantial, and clinicians must employ strategies that have been proven to be effective in reducing hospital costs and length of stay without compromising patient outcomes. The most effective means to reduce the cost of VAP is preventing it altogether, and a multidisciplinary team approach is imperative for implementing and continuing a successful VAP prevention program. As members of the ICU and infectious diseases team, clinical pharmacists can play an integral role in VAP prevention and should aim to be more proactive in helping achieve goals that minimize episodes of HAIs.

Off-Label Disclosure Statement
In this article, the following off-label use of an antimicrobial agent is discussed: doripenem for the treatment of ventilator-associated pneumonia. OBJECTIVE: To present the etiology of VAP in the United States (including national resistance trends of common nosocomial pathogens) and review dosing strategies aimed to optimize pharmacokinetic-pharmacodynamic parameters of antimicrobial agents.
SUMMARY: The majority of nosocomial pneumonia cases are caused by gram-negative pathogens, most commonly P. aeruginosa, Enterobacter spp., A. baumannii, and K. pneumoniae. S. aureus is the most common gram-positive pathogen, with 55% of VAP isolates exhibiting methicillin resistance. Combination therapy is recommended when MDR pathogens and P. aeruginosa are suspected, although short-course therapy and deescalation should be considered when appropriate to reduce the risk of resistance. Optimized dosing strategies are important in increasing the probability of achieving successful outcomes. For example, when administering intravenous β-lactam therapy, prolonged infusion can be effective in increasing the T > MIC.
CONCLUSION: Clinicians need to be familiar with local antibiograms as well as regional resistance trends in order to choose appropriate therapy for VAP. Optimized dosing strategies can be effective in increasing the probability of attaining pharmacokinetic-pharmacodynamic targets predictive of successful clinical outcomes.

Introduction
Ventilator-associated pneumonia (VAP) is among the most common nosocomial infections originating in the intensive care unit (ICU), affecting 9% to 27% of all intubated patients. 1,2 The attributable mortality can be as high as 33% to 50%. 1,2 The risk of VAP is correlated to the length of stay (LOS) in the hospital or ICU as well as to the duration of mechanical ventilation. 2 Pseudomonas aeruginosa and multidrug-resistant (MDR) organisms account for over 20% of VAP infections, with higher rates observed in those with prolonged hospitalization. 3 Infection by these problematic pathogens is associated with increased mortality, duration of mechanical ventilation, and hospital LOS. 3 Therefore, when managing patients at high risk for VAP, it is important to recognize the local epidemiology and resistance trends in order to select the most appropriate initial antimicrobial therapy.

Etiology of Hospital-Acquired Pneumonia
Surveillance data from the National Healthcare Safety Network (NHSN, formerly the National Nosocomial Infections Surveillance System) have shown that gram-negative pathogens are the predominant cause of nosocomial pneumonia, accounting for approximately 70% of infections. 4 Among the infections caused by gram-negative pathogens, P. aeruginosa is the leading cause (accounting for approximately 20%) followed by Enterobacter spp., Klebsiella pneumoniae, and Acinetobacter baumannii. 4 The proportion of infections due to Acinetobacter has nearly doubled over the past 2 decades (from 4% in 1986 to 7% in 2003). However, there has been a gradual trend of increasing infections due to grampositive pathogens, mainly Staphylococcus aureus.
The etiology of VAP can vary based on (a) local epidemiological trends as well as (b) the timing of onset of infection. According to the 2006-2007 NHSN data, the most common pathogen associated with VAP is S. aureus (24.4%) followed by P. aeruginosa (16.3%), Enterobacter spp. (8.4%), A. baumannii (8.4%), and K. pneumoniae (7.5%) ( Table 1). 5 The time of onset is also an important predictor of causative pathogens. Early-onset VAP, defined as VAP occurring within the first 5 days of hospitalization, is caused by enteric gram-negative bacteria (including Escherichia coli, K. pneumoniae, and Enterobacter spp.), Haemophilus influenzae, Streptococcus pneumoniae, and methicillin-susceptible S. aureus (MSSA). 2,6 Late-onset VAP, defined as VAP occurring after 5 days of hospitalization, is more likely to be caused by MDR pathogens, 2,6 including those associated with early-onset VAP as well as P. aeruginosa and A. baumannii. The variety and complexity of pathogens associated with VAP make choosing an appropriate initial therapy challenging.

Appropriate Antimicrobial Therapy for VAP
The American Thoracic Society (ATS) and the Infectious Diseases increased prevalence of Acinetobacter infections and a lack of other effective agents. It is important to note that colistin should not be used as monotherapy, since resistance to this agent can occur frequently when used alone. 14,15 The prevalence of extended-spectrum β-lactamase (ESBL)producing gram-negative E. coli and K. pneumoniae has increased in the past several years (Figure 2). 4 These bacteria are resistant not only to third-generation cephalosporins but to other classes of antibiotics as well. 16 ESBL production can be conferred chromosomally or via a plasmid-plasmid-mediated resistance often carries resistance to aminoglycosides and other drug classes as well. 2 Therefore, when treating infections due to ESBL-producing E. coli and K. pneumoniae, cephalosporins, including fourthgeneration cephalosporins, should not be given as monotherapy. There is also a high likelihood of resistance to fluoroquinolones and aminoglycosides. 17 These strains are usually susceptible to carbapenems, which are, therefore, the preferred class for treating these infections. Extensive clinical experience also supports the use of carbapenems for these infections. 2,17 However, it is important to note that multiple mechanisms for resistance to carbapenems have been identified and the prevalence of resistant strains should be carefully monitored. 18

Treatment Strategies to Minimize Resistance Development
Hospital infections will be more challenging given the rising resistance rates observed in nosocomial pathogens coupled with the lack of antimicrobial agents in development targeting these pathogens. 10 Therefore, the available agents must be used judiciously and effectively to reduce the risk of further development of resistance. Treatment strategies that may reduce the further development of resistance, while achieving similar clinical outcomes, include short-course therapy and de-escalation or streamlining therapy.
Society of America (IDSA) guidelines on the management of VAP released in 2005 recommend combination therapy for late-onset infections or when P. aeruginosa, A. baumannii, or an MDR pathogen is suspected. 2 Gram-negative coverage should include an antipseudomonal cephalosporin or an antipseudomonal carbapenem or an antipseudomonal β-lactam/β-lactamase inhibitor. In addition, an antipseudomonal fluoroquinolone or an aminoglycoside is recommended to ensure adequate coverage. If methicillinresistant Staphylococcus aureus (MRSA) is also suspected, the regimen should include either vancomycin or linezolid.
The appropriate selection of specific agents depends on local susceptibility trends. Therefore, it is critical to be familiar with the antibiogram of the institution as well as specific hospital wards. As discussed earlier, national surveillance data indicate a predominance of S. aureus as causative pathogen for VAP. 5 Moreover, MRSA now accounts for nearly 55% of all S. aureus VAP isolates. This is important, as MRSA infections are associated with increased mortality, LOS, and hospital costs as compared with MSSA infections. [7][8][9] Among the gram-negative pathogens, the most concerning are MDR P. aeruginosa, carbapenem-resistant Acinetobacter spp., and third-generation cephalosporin-resistant E. coli and Klebsiella spp. 10 P. aeruginosa exhibits elevated rates of resistance to fluoroquinolones and carbapenems and has been trending toward greater resistance to other antimicrobial classes ( Figure  1). 11 Over one-third of Acinetobacter isolates from VAP patients exhibit resistance to carbapenems-moreover, carbapenemresistant isolates typically exhibit resistance to multiple antimicrobial classes. 5 MDR Acinetobacter isolates commonly have low susceptibility rates to fluoroquinolones, aminoglycosides, and β-lactams, including carbapenems. 12 Therefore, for infections due to Pseudomonas or Acinetobacter, it is particularly important to know the local antibiogram in order to select the most appropriate combination of agents.
Recommendations for treating infections due to Acinetobacter range from the use of combination therapy with an antipseudomonal β-lactam plus an aminoglycoside to combination therapy with colistin plus 1 or more other agents. 13 The resurgence in the use of colistin in hospitals is likely the result of the  Antimicrobial agents can be divided into those that exhibit concentration-dependent bacterial killing or time-dependent bacterial killing.
For concentration-dependent agents, the PK/PD parameters predictive of successful clinical outcomes include the peak to minimum inhibitory concentration (MIC) ratio (C max :MIC for aminoglycosides) or the area under the concentration-time curve (AUC:MIC for fluoroquinolones). This was illustrated in a pivotal study by Forrest et al. who evaluated the clinical and microbiologic success rates in nosocomial pneumonia patients based on drug exposure following fluoroquinolone therapy. 24 For patients with an AUC:MIC ratio below 125, microbiologic success rates were consistently below 40% ( Figure  3). For those with an AUC:MIC ratio above 125, microbiologic success rates were greater than 80%. It is important to recognize that meeting the PK/PD target does not necessarily guarantee a successful outcome but only predicts a greater chance of clinical success. Patient and pathogen factors can also impact the probability of a successful outcome.
For time-dependent agents such as the β-lactams, the PK/ PD parameter predictive of clinical success is the time above the MIC (T > MIC). The T > MIC required for clinical success can vary depending on the particular antimicrobial class. 25 The carbapenems require a T > MIC of 40% for maximal effect while the cephalosporins require T > MIC of 60% to 70%. 25 This variation among the classes can reflect differences in their bactericidal activity as well as the post-antibiotic effect of the agents.
As mentioned earlier, when P. aeruginosa or MDR pathogens are suspected, initial combination therapy increases the probability of providing adequate coverage. However, once the culture and susceptibility results are available and the patient shows signs of improvement, de-escalation of therapy to narrow coverage to only what is necessary should be considered. This is appropriate if an anticipated organism (such as MRSA, P. aeruginosa, or Acinetobacter spp.) was not recovered or if the organism was susceptible to a more narrow-spectrum agent than initially used. 2 By decreasing total antimicrobial usage, de-escalation of therapy can potentially reduce the risk of emergence of resistance to agents that are no longer deemed necessary for clinical success.

Optimizing Pharmacokinetic-Pharmacodynamic Parameters
The main goals of antimicrobial therapy are to maximize efficacy while minimizing the development of resistance. Strategies that can help achieve these goals include antimicrobial stewardship, infection control, and optimizing pharmacokinetic/pharmacodynamic (PK/PD) parameters.
This review will not discuss antimicrobial stewardship or infection control tactics. A number of publications provide a thorough understanding of the benefits of antimicrobial stewardship. [20][21][22] The recent guidelines released by the IDSA and the Society for Healthcare Epidemiology of America (SHEA) state the importance of the clinical pharmacist in implementing an antimicrobial stewardship program at institutions. 20 Infection control is traditionally not the focus of clinical pharmacists, but given the new mandates affecting reimbursement for hospitalacquired infections (HAIs) and heightened efforts to reduce HAIs, all health care personnel should be aware of infection control tactics. The SHEA and IDSA recently released a compendium of strategies to prevent various health care-associated infections in acute care hospitals that can be a valuable resource for hospitalbased clinicians. 23 This review will focus on optimizing PK/PD parameters. In experiments with a wild-type strain, a large reduction in bacterial burden was observed within the first 24 hours of each regimen tested, although substantial regrowth occurred after 3 days for regimens that maintained T > MIC of 100% and had a C min :MIC of 1.7. Suppression of resistant subpopulations required T > MIC of 100% and a C min :MIC ratio of 6.2 or greater. Achieving these levels would be impractical in a clinical setting, which illustrates the difficulty in suppressing the development of resistance for this problematic pathogen. Lower concentrations of meropenem and the addition of tobramycin was effective in suppressing the development of resistance, confirming the importance of combination therapy for patients suspected with infections by P. aeruginosa.
infusion period can be used to increase the T > MIC and lower the peak concentration. 26,27 The infusion period can be extended through either (a) continuous infusion (i.e., administering a loading dose and then a pump to administer the total daily intravenous dose over a 24-hour period), or (b) prolonged infusion (i.e., administering the same dose and dosing interval but increasing the duration of infusion, such as from 30 minutes to 3 hours).
The use of prolonged infusion has been studied extensively with doripenem. In 1 study, the concentration-time profiles of a 500 mg dose were compared with various infusion times ranging from 1 hour to 6 hours ( Figure 4). 28 The impact of longer infusion times were then evaluated by determining the probability of meeting the T > MIC target of 40%. For pathogens with an MIC of 1 µg/mL, 1-hour and 3-hour infusions were effective in meeting the PK/PD target. However, for pathogens with an MIC of 2 µg/mL, a 1-hour infusion had a 77% probability of meeting the PK/PD target compared a 100% probability with a 3-hour infusion. For pathogens with an MIC of 4 µg/mL, a 5-hour infusion was required to achieve a 99% probability of meeting the PK/PD target.
The PK/PD study with doripenem was instrumental in designing a clinical trial comparing doripenem with imipenem for the treatment of VAP. 29 Doripenem (500 mg every 8 hours; n = 264) was administered via a 4-hour infusion and compared with an imipenem treatment (500 mg every 6 hours via a 30-minute infusion or 1,000 mg every 8 hours via a 60-minute infusion; n = 267). In the clinically evaluable population, there was no significant difference in overall clinical success between the 2 treatment groups (68.3% for doripenem vs. 64.8% for Curbing Resistance Development: Maximizing the Utility of Available Agents PK/PD Profile of Doripenem 500 mg

Summary
VAP caused by P. aeruginosa and MDR pathogens presents a challenge to clinicians when selecting appropriate initial antimicrobial therapy. Current recommendations point to combination therapy to ensure adequate coverage of potential pathogens followed by de-escalation of therapy once culture and susceptibility results become available. Given the dearth of new antimicrobial agents in the pipeline, de-escalation of therapy can be critical in reducing the potential for development of resistance against available agents and prolonging their effectiveness. Optimized dosing strategies that take into account PK/PD parameters can also be important in increasing the probability of successful outcomes as well as in reducing the risk of development of resistance. Certain tactics, such as prolonged infusion of β-lactam agents, can improve the probability of PK/PD target attainment, although this does not necessarily guarantee a successful outcome.

Introduction
Although largely considered preventable, ventilator-associated pneumonia (VAP) is among the most common nosocomial infections acquired by adults and children in the intensive care unit (ICU), affecting approximately 9% to 27% of patients undergoing mechanical ventilation. 1 With an incidence that can be as high as 10 episodes per 1,000 ventilator-days, 2 VAP is associated with an attributable mortality of 33% to 50%. 1 In addition, the economic burden is substantial due to extended periods of mechanical ventilation, prolonged length of stay (LOS) in the ICU and hospital, overconsumption of antimicrobial agents, and increased health care costs. 3 Given the economic impact of VAP and that it is generally preventable in most cases, renewed efforts must be made by all health care personnel to implement and adhere to strategies that prevent VAP or minimize the risk of VAP. It is critical for health care professionals and administrators to be aware of strategies that have been proven effective in improving resource utilization and to adopt strategies that can be appropriately implemented at their institutions.

The Clinical and Economic Costs of VAP
A number of studies have evaluated the clinical and economic impact of VAP. The Society for Healthcare Epidemiology of America (SHEA) released guidelines in 2007 on how to make a business case for infection control programs at hospitals. 4 The report included costs attributable to different types of hospitalacquired infections (HAIs), including VAP, catheter-related bloodstream infection, coronary artery graft bypass surgery-associated surgical site infection, and catheter-related urinary tract infection. VAP was found to be associated with the highest attributable costs (an additional $23,000 per episode on average), compared with bloodstream infection ($18,432), surgical site infection ($17,944), and urinary tract infection ($1,257). An episode of VAP was also associated with a mean increase in the LOS by nearly 10 days.
A prospective, cohort study conducted by Warren et al. at a community hospital evaluated the impact of VAP on clinical outcomes and costs. 5 The study included patients from the medical and surgical ICU from 1998 to 1999 and compared outcomes in patients who developed VAP with those who did not develop VAP. A total of 819 patients were included in the analysis, of which 127 had developed VAP. Patients with VAP were found to have a higher APACHE II (Acute Physiology and Chronic Health Evaluation) score, higher rate of congestive heart failure on admission, higher rate of hemodialysis, and longer duration of central venous catheter use and mechanical ventilation (Table 1). When considering patient outcomes, the LOS was significantly longer for patients with VAP-over 20 days longer on average for both ICU LOS and hospital LOS. Total hospital costs for patients with VAP were $48,948 higher. When these costs were adjusted for disease severity, the attributable cost was $11,897 for each case of VAP. Mortality rates were also significantly higher in patients with VAP (50% vs. 34%, P < 0.001).
Muscedere et al. reviewed the published literature and institutional data to assess the impact of VAP on the Canadian health care system. 2 In this study, the incidence of VAP in Canada was estimated at 10.6 cases per 1,000 ventilator-days, which equated to approximately 4,000 VAP cases each year. VAP increased the mean ICU LOS by 4.3 days per episode and resulted in a total excess cost of CAN $46 million (about $11,500 per VAP case). The attributable mortality was estimated to be 5.8%, or 232 deaths each year. The authors emphasized that eradication of this preventable infection will significantly impact VAPassociated mortality rates and health care resources. The excess ICU LOS reported by Muscedere et al. was much less than what was reported in the Warren study (22 additional days by VAP patients); 5 this difference may be due to differences in the methodology and patient selection of the 2 studies. The Warren study compared all ICU patients (with and without VAP) requiring > 24 hours of mechanical ventilation during a set time period, while the Muscedere analysis was based on 1 matched cohort study (cases included patients requiring > 48 hours mechanical ventilation and developed VAP).

Cost Distribution of VAP
The excess costs associated with VAP can be directly linked to the prolonged LOS. Warren et al. analyzed the cost distribution associated with VAP and determined that room and nursing costs accounted for nearly 50% of the total hospital costs. 5 Pharmacy costs, including antimicrobial therapy, accounted for approximately 20% of the total costs with the remainder of costs attributed to operating room, laboratory, respiration therapy, radiology, and other expenses.
The cost distribution among ICU infected patients with and without VAP was also evaluated in a matched cohort study in Switzerland. 6 The matching procedure identified 97 pairs of mechanically ventilated patients and revealed that the largest proportion of costs (approximately 75%) for patients with and without VAP was related to the costs of the ward (or fixed costs) (Figure 1). These costs also included the expenses related to physicians and nurses. For patients who remained free of any ICU-acquired infection, the total cost was less than one-third of the cost for ICU patients with VAP.

Cost Burden: Impact of Resistance
The increasing prevalence of resistant and multidrug-resistant pathogens can impact the cost of managing patients with VAP. Antimicrobial resistance can increase the risk of inappropriate therapy, which potentially increases mortality rates as well as LOS and duration of mechanical ventilation. [7][8][9] A retrospective, cohort study was conducted to compare the clinical and economic outcomes for patients with early-onset VAP infected with methicillin-resistant S. aureus (MRSA) versus methicillin-susceptible S. aureus (MSSA). 10 A total of 154 patients with S. aureus infections were included (59 patients with MRSA) in the multivariate analysis. MRSA infections were associated with a significant increase in mechanical ventilation days and ICU LOS ( Table 2) and an insignificant increase in total LOS (3.8 days more) and total costs ($7,731 higher). These results imply that there is a greater use of resources for managing patients with MRSA-related VAP compared with patients with MSSA-related VAP. Strategies should, therefore, be employed to quickly diagnose patients with VAP caused by MRSA to reduce morbidity and hospital costs.

Clinical Burden: Initial Inappropriate Therapy
Initial inappropriate therapy for VAP is associated with significantly higher mortality rates than initial appropriate therapy. [7][8][9] In a retrospective, observational cohort study, the 30-day mortality rates were determined in 76 patients with VAP caused by potentially resistant gram-negative bacteria (P. aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia). 11 Those who received Collaborative Strategies for Improving Clinical Resource Utilization: How Pharmacists Can Make a Difference

Improving Resource Utilization Through Appropriate Antimicrobial Therapy
Ideal therapy for VAP involves appropriate initial therapy while avoiding unnecessary antimicrobial use. These goals have been emphasized in the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guidelines pertaining to management of hospital-acquired pneumonia. 1 The ATS/ IDSA guidelines recommend early, appropriate antimicrobials in adequate doses while avoiding excessive antimicrobial use through de-escalation of initial therapy and shortening the duration of therapy to the minimum effective period. The guidelines further state that antimicrobial selection and therapeutic adjustment should be based on microbiologic cultures and clinical response of the patient.
Selecting the appropriate initial therapy can be challenging, given the variety of causative pathogens and the difficulty in predicting their susceptibility profile. Because of the importance of appropriate initial antimicrobial therapy for VAP, the ATS/ IDSA guidelines recommend initial combination therapy when a multidrug-resistant pathogen or P. aeruginosa is suspected. 1 However, to limit the excessive use of antimicrobials, the guidelines recommend de-escalation of therapy once microbiologic results are available.

De-escalation of Therapy
De-escalation of therapy reduces the unnecessary use of antimicrobials and has the potential to decrease the risk of development of resistance without affecting clinical outcomes. How to de-escalate is still controversial; while more research is needed to arrive at the optimal approach, several steps have been outlined on adopting this strategy. 1,13,14 The following steps can serve as a useful guide in adopting a strategy of de-escalation. However, adjustments to this model should be made based on the individual patient characteristics and specific conditions at each institution.
Step 1. Obtain microbiologic samples. Microbiologic samples should be obtained as soon as VAP is suspected due to the significant time needed to obtain culture and susceptibility results.
Step 2. Begin empiric antimicrobial therapy. Therapeutic selection should be based on patient risk factors for MDR pathogens as well as local susceptibility patterns. Patients should be carefully monitored for clinical improvement based on their temperature, white blood cell count, chest X-ray, PaO 2 /FiO 2 , organ function, and hemodynamic parameters.
Step 3. Evaluate and de-escalate. Response to appropriate therapy can take 48 to 72 hours, so the selected antimicrobial regimen should not be changed during this time unless progressive deterioration of the patient occurs or initial microbiologic results suggest otherwise. Once culture results and susceptibility profiles are obtained, de-escalation of therapy can be considered.
If the patient shows clinical improvement, it may be possible to narrow (de-escalate) the antimicrobial spectrum based on the microbiologic results. After 7 to 8 days of therapy, the patient should be re-assessed for the need of continued therapy. An exception to short duration of therapy for VAP includes appropriate antimicrobial therapy (n = 59) within 24 hours of bronchoalveolar lavage sampling had a significantly lower 30-day mortality rate compared with those who received inappropriate therapy (n = 17; 17.2% vs. 50.0%, P = 0.005). Due to an increased mortality and shorter hospital LOS of patients with inappropriate antimicrobial therapy, there was no significant difference in total hospital costs between the 2 patient populations.
A meta-analysis conducted by Kuti et al. evaluated the impact of initial inappropriate antibiotic therapy on mortality of VAP patients. 12 All studies published from 1966 to December 2006 were included if they met all of the following criteria: (a) observational studies, (b) compared patients receiving appropriate and inappropriate antibiotic therapy, and (c) reported data on incidence of mortality. Appropriate therapy was defined as treatment with at least 1 antibiotic having in vitro activity against the cultured pathogen. A total of 9 studies (813 total patients) met the inclusion criteria. Unadjusted mortality data revealed that inappropriate therapy significantly increased the risk of death in patients with VAP (odds ratio [OR] = 2.34, 95% CI = 1.51-3.63). An adjusted analysis was performed that included only those studies that used an appropriate analytic method to estimate an adjusted effect, adjusted ORs, and CIs. Three studies (323 patients) were included in the adjusted mortality analysis and showed similar results (OR = 3.03, 95% CI = 1. 12-8.19). The authors suggest that the data show a clear association between inappropriate therapy and mortality in VAP patients. Clinicians should attempt to adopt protocols that help ensure initial appropriate therapy for these patients. a once-daily respiratory therapy-driven weaning attempt, and conversion from a nasogastric to an orogastric tube whenever possible. In 2003 (prior to guidelines), there were 1,600 days of ventilator support compared with 703 days of ventilation in 2004 (following guideline implementation). Following implementation of these guidelines, the incidence of VAP decreased from 6.9 per 1,000 ventilator-days to 2.8 per 1,000 ventilator-days. This had a significant impact on resource utilization given that VAP patients had, on average, greater hospital LOS (an additional 25.4 days per episode), greater ventilator days (an additional 11.3 days per episode), and greater hospital charges (an additional $233,000 per episode). This study illustrates the importance of considering improved preventative strategies as an effective means to reduce resource utilization among patients with VAP.

Multidisciplinary Team Model for VAP Prevention
Improving resource utilization when managing patients with VAP will require greater efforts in education of health care personnel, improved early and accurate diagnosis, appropriate empiric therapy, and the use of prevention measures. The goals of VAP prevention programs are to decrease morbidity and mortality associated with these infections and to reduce hospital costs. Achieving these goals will require implementing tactics that reduce the risk of infection, which can include improved infection control, reduced inappropriate antimicrobial use, and limiting device days. Initially, it may be practical for an institution to focus on implementing a few proven cost-effective strategies.
The Institute for Healthcare Improvement (IHI) 100,000 Lives Campaign recommends a VAP "bundle" that includes 4 components: (a) elevation of head of the bed to between 30 degrees and 45 degrees, (b) daily "sedation vacations" and assessment for readiness to extubate, (c) prophylaxis for peptic ulcer disease, and (d) prophylaxis for deep vein thrombosis. 20 Initial reports have shown a dramatic decrease in VAP rates once these tactics were implemented at institutions. 21,22 VAP prevention programs require widespread support within the institution for implementation and adherence. Prevention programs should be multidisciplinary and evidence-based and should translate prevention strategies into hospital practice focused on patient safety and quality improvement. 23 Dr. Donald infections caused by nonfermenting gram-negative pathogens, such as P. aeruginosa or Acinetobacter spp., which may require longer antimicrobial courses (e.g., 15 days or longer). 15 If the patient shows no or little sign of clinical improvement, the patient should be re-assessed based on pathogen resistance to therapy, the presence of a complication (such as an abscess), a noninfectious diagnosis, or inadequate tissue penetration of the drug to the site of infection.

Use of Institutional Guidelines in VAP Management and Prevention
The use of VAP management guidelines can be effective in improving appropriate antimicrobial therapy and decreasing resource utilization. Recent evidence-based clinical guidelines by Muscedere et al. incorporate many of the aspects discussed in this review and can serve as an important reference when managing patients with VAP. 16 A recent report from Canada assessed the value of de-escalation of therapy once culture results became available. 17 All 740 patients included in the study received empiric broad-spectrum therapy and were then stratified depending on if they received targeted therapy based on culture results. Targeted therapy in this study was defined as a narrower spectrum of antimicrobial therapy based on culture and susceptibility results or discontinuation of antibiotics when cultures were negative. For those with positive cultures (n = 412), the clinical progression of infection, multiple organ dysfunction scores, and mortality were not significantly different between the 2 patient populations. However, those who receive targeted therapy (n = 320) had more days alive and off broad-spectrum antimicrobials (14.5 vs. 13.2 days, P = 0.04). Those with negative cultures (n = 327) and treated with targeted therapy (n = 230) had more days alive and off broadspectrum therapy (15.9 vs. 13.1 days, P < 0.001) and fewer days on mechanical ventilation (9.8 vs. 14.7 days, P = 0.03). The authors concluded that targeted therapy resulted in less antimicrobial use without any clinical compromise.
A report from a university-affiliated teaching hospital in Seattle, Washington, compared outcomes before and after the implementation of VAP management guidelines based on local microbiologic data. 18 The guidelines promoted the use of quantitative bronchoscopy for diagnosis and initiated empiric therapy based on local microbiologic findings and resistance patterns. Therapy was then tailored based on culture results, and the duration of therapy was carefully considered based on clinical response. Following implementation of the guidelines, there were significant increases in the rate of tailoring therapy based on culture results and the use of definitive therapy, as well as a decrease in the mean duration of therapy ( Table 3). The implementation of the guidelines led to a significant improvement in antimicrobial use practices, although no improvement was observed in the allcause mortality rate of these patients.
Finally, a university teaching hospital in Kansas reported the effects of implementing evidence-based VAP prevention strategies on the incidence of infection in ventilated trauma patients. 19 The VAP prevention protocol was modified to include elevation of the head of the bed, twice-daily chlorhexidine oral cleansing,  Craven, in his guidelines for VAP prevention, suggests that a prevention program be led by a "champion leader" while other core members include administration, nursing, infectious disease and critical care physicians, respiratory therapists, and microbiologists, among others. 23 Although clinical pharmacists are not specifically listed, several reports have described and documented the impact of critical care pharmacists within a multidisciplinary ICU team. [24][25][26][27] Evaluations of clinical pharmacists in the ICU setting have demonstrated the potential for improved patient outcomes and cost savings in critically ill patients, including those with VAP. [25][26][27] One of the greatest barriers to implementing a prevention program is gaining administrative support and funding. However, as previously described, there is a wealth of information available demonstrating the high costs of these infections. This aspect should be emphasized when presenting to the administrators the need for improved prevention programs that will lead to improved clinical outcomes and decreased resource utilization. Today's environment of increased transparency and accountability at hospitals should also provide incentive to implement strategies that lead to fewer cases of VAP.

Summary
When managing patients with VAP, clinicians must find a balance between (a) initiating appropriate therapy that provides adequate coverage, and (b) avoiding the overuse of antimicrobial agents. This approach will be important in achieving successful clinical outcomes while efficiently using scarce hospital resources. Strategies aimed at reducing hospital LOS will be most effective in improving resource utilization for patients with VAP. However, the greatest reduction in hospital costs will be through the implementation of preventative strategies that effectively reduce the actual number of VAP episodes. A multidisciplinary team approach will be critical in the success of these programs, and clinical pharmacists can play an integral role as part of the critical care team.
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